Endosseous implant

ABSTRACT

Endosseous implant to be applied to a human or animal bone, wherein the surface of the implant is made from titanium or a titanium alloy, said implant having a smooth or rough surface texture, which is characterized in that said surface has been treated with at least one selected organic phosphonate compound or a pharmaceutically acceptable salt or ester or an amide thereof; process for producing said implants.

The present invention relates to a metallic endosseous implant made fromtitanium or a titanium alloy to be applied to a human or animal bone,said implant having a smooth or rough surface texture, and wherein saidsurface has been treated with at least one selected organic compoundcarrying one or more phosphonic acid group [—P(O)(OH)₂] or a derivativethereof, preferably as a pharmaceutically acceptable salt or ester oramide thereof. It has been shown that such chemically modified surfacesurprisingly enhances the bone bonding strength. Implants according tothe present invention may be used as prostheses in medicine, morespecifically in orthopaedics, for replacing or strengthening broken ordiseased bones, and in dentistry, for anchoring artificial teeth and foranchoring of bone anchored hearing prosthesis.

Implants which are used as prostheses in medicine for replacing orstrengthening broken or diseased bones or as artificial teeth are known.These implants must be made of a non-corrosive material and must becompatible with the surrounding tissue without producing immunologicreactions effecting rejection by the body. In the following. the terms“surface” or “contact surface” refer to the titanium or a titanium alloyimplant surface not yet treated according to the present invention andthe term “modified surface” to the surface treated according to thepresent invention.

It is known that to implant devices in the form of screws, plates,nails, pins, and specially formed parts into the skeletal structure ofhumans and animals as artificial prosthetic is a means for permanentreplacement of missing structural parts or as permanent anchoringdevices. An excellent “osseointegration ” is required for thosesituations where the implanted device should remain permanently adheredto the contacting bone surface.

It is generally known to use titanium metal or titanium alloys for suchimplants. When carefully produced, the titanium implant with its surfaceoxide exhibits biocompatibility in the sense that it remains passive forbone regeneration and does not per se induce adverse reactions such asinflammation or soft tissue generation or encapsulation. The interfaceobtained between the implant and the bone tissue normally consists of aprotein layer of about 100 nm to 1 μm thickness preventing the bonetissue from being in direct molecular contact with the implant.

The actual state of the art for endosseous implants is based ondifferent approaches, for example (i) the creation of a suitableroughness of the implant surface giving a mechanical interlockingbetween bone and implant and/or (ii) coating the titanium or titaniumalloy surface of the implant, e.g. with an artificial hydroxyapatite forimproving the healing process and the bone-implant intimate contact.

It is known that a high surface roughness on titanium implants increasesthe mechanical stability of the implant in the bone tissue. Mechanicalsurface treatment significantly alters the topography, while the surfacechemistry remains substantially unchanged. The disadvantages of animplant with a high surface roughness are that a purely mechanicalanchoring is very sensible to micromotions which may lead to adeterioration of the mechanical anchorage and that the osseointegrationtime of the implant is relatively long.

Coating the surface of the implant with an artificial hydroxyapatitedecreases the osseointegration time. However, it is very difficult, ifnot impossible, to produce hydroxyapatite coatings with a long termstability on load bearing implants. The interface between the coatingand the implant is often disrupted or the coatings are flaked off.

U.S. Pat. No. 5,733,564 suggests to use selected bisphosphonates whichare known drug substances for the promotion of bone tissue formation bycoating titanium metal surfaces of prostheses or implants with thesecompounds.

It has now been found that if the surface of a titanium or a titaniumalloy endosseous implant has been treated with at least one selectedorganic compound as defined herein below carrying one or more phosphonicacid groups or a derivative thereof, preferably an ester, an amide or asalt thereof, as defined herein below, said surface shows a surprisinglyimproved bone bonding strength and a surprisingly shortenedosseointegration time compared to the non treated surface and does nothave the disadvantages as known for surfaces having a hydroxyapatitecoating.

The present invention is defined in the claims. The present inventionspecifically refers to an endosseous implant to be applied to a human oranimal bone, wherein the surface of the implant is made from titanium ora titanium alloy, said implant having a smooth or rough surface texture,which is characterized in that said surface has been treated with atleast one organic compound corresponding to the general formula (I):A-[P(O)(OH)₂]_(p)  (I),

-   or a pharmaceutically acceptable derivative thereof, which is    preferably an ester, an amide or a salt thereof, wherein A means A₁    or A₂, and-   A₁ is a residue of a linear, branched or cyclic, saturated or    unsaturated, hydrocarbon residue with n carbon atoms, whereby said    residue may be substituted by hydroxyl and/or carboxyl and    optionally further interrupted by one or more oxygen and/or sulphur    and/or nitrogen atoms, carrying p phosphonic acid groups, wherein n    is a number from 1 to 70, preferably 1 to 40, preferably 1 to 22,    and-   when n is 1 and p is 2: A is —CH₂—, or-   when n is 1: p is 3 or 4, preferably 3, or-   when n is 2 to 10: p is 2, provided each phosphonic acid group or    phosphonic acid ester group is bound to a different carbon atom    within the same molecule; or-   when n is 2 to 10: p is 3, 4, 5 or 6, preferably 3, 4 or 5,    preferably 3 or 4; or-   when n is 11 to 70: p is 2, 3, 4, 5 or 6, preferably 2, 3, 4 or 5,    preferably 2, 3 or 4;-   or A means A₂ and-   A₂ is a residue of an amino acid or of a sequence of amino acids    resp. of a protein or of a polypeptide, preferably a residue of the    superfamily of Transforming Growth Factor beta (TGF-β); or a residue    of a specific drug molecule, wherein each residue A₂ carries p    phosphonic acid groups, and-   p is 1 to 6, preferably 1, 2, 3 or 4, preferably 1, 2, or 3, when A₂    is a residue of an amino acid or of a sequence. of amino acids resp.    of a protein or of a polypeptide; or-   p is 1 or 3-6, preferably 1, when A₂ is a residue of a specific drug    molecule originally not bearing any phosphonic group, optionally    falling under the definition given for A₁.

The present invention further refers to a process for producing theimplant according to the present invention which is characterized inthat said surface is treated with at least one organic compound offormula (I) or a derivative thereof, which is preferably an ester, anamide or a salt thereof.

It is assumed that the phosphonate compounds as specified herein,especially as acids or salts, form a covalent bond with the surface ofthe implant thereby improving the osseointegration properties of saidsurface to a remarkable and unexpected extent. The present inventionhowever is not bound to this explanation.

A₁ preferably is a saturated hydrocarbon residue of the formula—(C_(n)H_(2n+2−p))—, wherein n means 1 to 70, preferably 1 to 40,preferably 1-22. Preferred is the free acid or the salt form of thecompound of formula (I), preferably where the pharmaceuticallyacceptable salt is an alkali salt, preferably of sodium or potassiumsalt. If the pharmaceutically acceptable ester is used, the isopropylphosphonate or ethyl phosphonate esters are preferred, examples of suchesters are: tetra isopropyl methylenediphosphonate, hexaethylethane-1,1,2-triphosphonate, hexaisopropyl butane-1,1,4-triphosphonate,hexaisopropyl pentane-1,1,5-triphosphonate, hexaisopropylpentane-2,2,5-triphosphonate, hexaisopropyl hexane-2,2,6-triphosphonate,octaisopropyl propane-1,1,3,3-tetraphosphonate, octaisopropylheptane-1,4,4,7-tetraphosphonate, octaisopropylnonane-1,5,5,9-tetraphosphonate.

The metallic surface of the endosseous implant to be treated accordingto the present invention may be made from titanium or a titanium alloyas known to be used for the production of endosseous implants. Titaniumalloys may be made from titanium and any other metal known to form analloy with titanium, such as chromium, niobium, tantalum, vanadium,zirconium, aluminium, cobalt, nickel and/or stainless steels. Suchtitanium metal alloys for making implants are known per se and aredescribed for example in Breme et al., Metals as Biomaterials, pp. 1-71(1998) the contents of which are incorporated herein by reference.

Implants according to the present invention may be in the form ofscrews, plates, nails, pins, and specially formed parts and may be usedas prostheses in medicine, more specifically in orthopaedics, forreplacing or strengthening broken or diseased bones, and in dentistry,for anchoring artificial teeth and for anchoring of bone anchoredhearing prosthesis into the skeletal structure of humans and animals.The surface area of the implant which is to be bound to the body tissueresp. bones, may have a smooth or rough surface texture. Such surfacetextures are known and can be obtained for example by treating thesurface mechanically and/or with acids and/or electrolytically and/orwith a glow-discharge plasma and/or plasma spraying and/or or by electromachining. Such materials and processes have been described in differentpublications, for example in B. -O. Aronsson et al., J. Biomed. Mater.Res. 35 (1997), pp. 49f., the contents of which are incorporated hereinby reference.

Examples of compounds of formula (I) wherein A is a residue of asaturated hydrocarbon are polyphosphonic acids such asmethylenediphosphonic acid, ethane-1,2-diphosphonic acid,propane-1,3-diphosphonic acid, propane-1,3-diphosphonic acid,ethane-1,1,2-triphosphonic acid, butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, propane-1,1,3,3-tetraphosphonicacid, or nonane-1,5,5,9-tetraphosphonic acid.

Examples of compounds of formula (I) wherein A is a residue of a proteinresp. polypeptide in the form of a Transforming Growth Factor beta(TGF-β) in which are included the all members of the superfamily ofgrowth factors and particularly the TGF-β1, TGF-β2, TGF-β3, TGF-β4, andTGF-β5 as described for example in A. B. Roberts, M. B. Sporn, Handbookof Experimental Pharmacology, 95 (1990) pp. 419-472 or D. M. Kingsley,Genes and Development 8 (1994) p. 133-146, and references therein, wherethe peptide chain has been modified to contain an alkylphosphonic acidgroup or a derivative thereof, which is preferably an ester, an amide ora salt thereof. In this sense the compound of formula (I) represents aTransforming Growth Factor beta (TGF-β) as defined by the members of thesuperfamily of growth factors, preferably the TGF-β1, TGF-β2, TGF-β3,TGF-β4, and TGF-β5, wherein each time the peptide chain has beenmodified to contain at least one alkylphosphonic acid group or aderivative thereof, which is preferably an ester, an amide or a saltthereof.

Examples of compounds of formula (I) wherein A is a residue of a BoneMorphogenic Protein (BMP) (being a subfamily to the TGF family) e.g.,the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5, BMP-6, BMP-7 (OP-1),BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, as found forexample in J. M. Wozney et. al., Science 242 (1988) 1528-1534; A. J.Celeste et al., Proc. Natl. Acad. Sci. USA 87 (1990) 9843-9847; E.Özkaynak et al., J. Biol. Chem. 267 (1992) 25220-25227; Takao et al.,Biochem. Biophys. Res. Com. 219 (1996) 656-662; WO 93/00432; WO94/26893; WO 94/26892; WO 95/16035 and references therein, where thepeptide chain has been modified to contain an alkylphosphonic acid groupor a derivative thereof, which is preferably an ester, an amide or asalt thereof. These compounds are incorporated herein by reference. Inthis sense the compound of formula (I) represents a Bone MorphogenicProtein (BMP), preferably the BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b),BMP-5, BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12,BMP-13, wherein the peptide chain has been modified to contain at leastone alkylphosphonic acid group or a derivative thereof, which ispreferably an ester, an amide or a salt thereof.

Examples of compounds of formula (I) wherein A is a residue of an aminoacid are 2-amino-4,4-bis-(diethoxyphosphoryl)-butyric acid as describedfor example in O. Fabulet et al., Phosphorus, Sulphur Silicon andRelated Elements, 101, 225-234 (1995);2-amino-5-(diethoxyphosphoryl)-pentanoic acid as described for examplein I. G. Andronova et al., Russ. J. Gen. Chem. 66, 1068-1071 (1996);2-amino-4-phosphonobutyric acid as described for example in X. Y. Jiaoet al., Synth. Commun. 22, 1179-1186 (1992) and references therein.Further examples are all the principal twenty amino acids as describedfor example in L. Stryer, Biochemistry, 3rd edition (1988), pp. 17-22,where the amino acid is modified in an analogous way with analkylphosphonic acid group or a derivative thereof, which is preferablyan ester, an amide or a salt thereof, preferably wherein the compound offormula (I) is one of the principal twenty amino acids, preferablyarginine, glycine, aspartic acid, alanine, valine, proline, serine,threonine, cysteine or lysine, wherein the amino acid has been modifiedto contain at least one alkylphossphonic acid group or a derivativethereof, said derivative being preferably an ester, an amide or a saltthereof. These compounds are incorporated herein by reference.

Examples of compounds of formula (I) wherein A is a residue of a peptidecomprise but are not limited to RGD-containing peptides, RGDS-peptides,GRGDS-peptides, RGDV-peptides, RGDE-peptides, and/or RGDT-peptides. Suchpeptides are described for example in Y. Hirano, J. Biomed. MaterialsRes., 25 (1991), pp. 1523-1534 or in WO 98/52619 and references therein.Included within the scope of the present invention are also similarpeptides known to have specific biological activities such as cellattachment or cell attachment prevention, and which are prepared inanalogy with the peptides as mentioned above. In this sense the compoundof formula (I) is a RGD-containing peptide, preferably a RGDS-peptide, aGRGDS-peptide, a RGDV-peptide, a RGDE-peptide, and/or a RGDT-peptide,which has been modified to contain at least one alkylphosphonic acidgroup or a derivative thereof, which is preferably an ester, an amide ora salt thereof.

Preferred compounds of formula (I) are those containing a residue A₂ asdefined above, preferably a residue of an amino acid or of a sequence ofamino acids resp. of a protein or of a polypeptide, preferably a residueof the superfamily of Transforming Growth Factor beta (TGF-β),preferably a Bone Morphogenic Protein (BMP).

The following steps are recommended to be taken for producing theimplant according to the present invention, i.e. for treating thesurface of the implant with at least one compound of formula (I) above.The implant is first cleaned in a cleaning bath for removing unwantedmolecules resp. impurities from the surface. Preferably the implant isfirst treated with a degreasing agent, for example an organic solventsuch as alcohol, chloroform, and another organic solvent and/or aninorganic detergent such as an aqueous alkaline solution based on sodiumhydroxide or potassium hydroxide. Subsequently, the implant is carefullyrinsed in pure water, preferably in distilled ultra-pure water, havingpreferably a conductivity resistance of at least 15 Mohm*cm. Aftercleaning and rinsing, the implant is dried with flowing nitrogen gas orflowing dry or hot air and stored under controlled conditions.Alternatively after degreasing the implant can be further treated in aglow-discharge plasma for cleaning the surface. The clean surface of theimplant is then treated with at least one compound of formula (I) or anester or a salt thereof, i.e. with at least one such compound or amixture thereof. The compound or the mixture of said compounds isbrought onto the surface of the implant by any suitable means, likebrushing, spraying, dipping or evaporation, including glow-dischargeplasma assisted vapour deposition. The phosphonic acid compound or theester or the salt thereof is preferably dissolved in a polar solvent, sothat a solution with a concentration of from about 1.0×10⁻⁵ mol/10 ml to5×10⁻² mol/10 ml, preferably from about 5×10⁻⁴ mol/10 ml to 2.0×10⁻²mol/10 ml with reference to the weight of the solvent is obtained.Preferably the concentration is such that a partial or full (1% to 100%,preferably 50% to 100% of a) monomolecular layer is formed on theimplant surface. The preferred solvent is pure distilled water. Theimplant is left in contact with the solution for a sufficiently longtime, preferably for a few minutes up to a few hours. After that theimplant is carefully rinsed with pure water and packed with a plastic ormetallic clean packaging material preferably into an air tight packagingwhich preferably is evacuated or filled with an inert gas such asnitrogen or an inert liquid such as pure water as defined herein above.Said pure water may contain inorganic salts, preferably alkali salts,such as alkali chlorides, sulfates, phosphates, phosphonates, preferablythe sodium and/or potassium salts, and/or compounds of the formula (I)or an ester or a salt thereof, preferably in a concentration of fromabout 1.0×10⁻⁵ mol/10 ml to 5×10⁻² mol/10 ml, preferably from about5×10⁻⁴ mol/10 ml to 2.0×10⁻² mol/10 ml of solvent, which preferably isdistilled water.

Analytical investigations, e.g. X-ray Photoelectron Spectroscopyanalysis (XPS) or NMR, have shown that on contacting the phosphonic acidcompound of formula (I) with the titanium surface of the implant,immediate adsorption takes place. A strong bond is formed between thesurface and the phosphonic acid compound so that a chemical surfacemodification is obtained. Several different alkane polyphosphonic acidsas mentioned herein above were synthesized. Dental implants producedwith these compounds according to the present invention have shownexcellent results.

The compounds according to the general formula (I), wherein p is 3 to 6,preferably 3 or 4, and n is 4 to 70, preferably 4 to 40, preferably 4 to22, the salts or esters or amides thereof are new. Examples of suchcompounds are butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, or nonane-1,5,5,9-tetraphosphonicacid.

The compounds hexaisopropyl butane-1,1,4-triphosphonate andoctaisopropyl heptane-1,4,4,7-tetraphosphonate, resp. a mixture of thesecompounds, are obtained in that an alkalimetal, preferably sodium, tetralower alkyl methylenediphosphonate, preferably tetraisopropylmethylenediphosphonate, is reacting with at least a stoichiometricamount of a dihalomethane, preferably dibromomethane, in the presence ofan organic solvent having no active hydrogen atoms, preferably dryhexane or benzene or toluene.

The reaction is preferably carried out at a temperature within the rangeof 30° C. to 125° C., preferably 40° C. to 110° C., until the reactionis completed, which generally is within a time period of 10 to 48 hours,preferably 18 to 36 hours.

To the reaction product is then added the purified product oftriisopropylphosphite that has been reacted withdiisopropyl-3-bromopropane. The obtained mixture of compounds can thenbe separated in a conventional manner, for example by columnchromatography

In an analogous way, by reacting 1,4-dibromobutane in excess molar ratioin the range 1:6 to 1:0.5 with triisopropylphosphite, surprisingly thenew compounds hexaisopropyl pentane-1,1,5-triphosphonate andoctaisopropyl nonane-1,5,5,9-tetraphosphonate are produced. Further, inan analogous way the hexaisopropyl pentane-2,2,5-triphosphonate andhexaisopropyl hexane-2,2,6-triphosphonate were obtained by reactingequal parts of tetraisopropylethane-1,1-diphosphonate withdiisopropyl-3-bromopropylphosphonate.

The process is further characterised by that these products arehydrolysed to produce the analogous acids by refluxing them in molarexcess of HCl for a time comprised within 1 to 12 hours, preferably 1 to6 hours. The compounds are then preferably dried under vacuum over P₂O₅.

The following Examples illustrate but do not limit the presentinvention.

EXAMPLE 1

Methylenediphosphonic acid was synthesized according to U.S. Pat. No.3,400,176 and B. A. Arbusov, Pure Appl. Chem. 9 (1967), pp. 307-353 andreferences therein. The compound was characterized by NMR (¹H, ³¹P, ¹³C)mass spectroscopic elemental analysis and by its melting point. Allthese data are in accordance with the literature O. T. Quimby et al., J.of Organomet. Chem. 13, 199-207 (1968).

Propane-1,1,3,3-tetraphosphonic acid was synthesized from tetraisopropylmethylenediphosphonate. The tetraphosphonic acidic solution wasconcentrated under vacuum, dried over P₂O₅ under vacuum. The ¹H, ³¹P and¹³C NMR results (D₂O) are in accordance with the given literature data.

In an analogous manner propane-1,3-diphosphonic acid,ethane-1,1,2-triphosphonic acid, butane-1,1,4-triphosphonic acid,pentane-1,1,5-triphosphonic acid, pentane-2,2,5-triphosphonic acid,hexane-2,2,6-triphosphonic acid, pentane-1,1,5,5-tetraphosphonic acid,heptane-1,4,4,7-tetraphosphonic acid, or nonane-1,5,5,9-tetraphosphonicacid, are synthesized.

EXAMPLE 2

A) A sample made from titanium in the form of a circular plate of 14 mmin diameter, having a thickness of 1 mm, is produced in a conventionalmanner. The sample surface is provided with a smooth surface roughnessby mechanical polishing with diamond paste according to standardprocedures. By Atomic force microscopy the surface roughness wasmeasured to a S_(rms) value of ca 6 nm over a surface area of 400 squaremicrons.

B) The implant as produced in chapter A) above is then put into anaqueous solution of (i) methylenediphosphonic acid [1.5×10⁻³ mol per 10ml of distilled water], (ii) ethane-1,1,2-triphosphonic acid [1.2×10⁻³mol per 10 ml, in distilled water], (iii)propane-1,1,3,3-tetraphosphonic acid [6.2×10⁻⁴ mol per 10 ml, indistilled water], (iv) 1-hydroxyethylidenediphosphonic acid [1.4×10⁻³mol per 10 ml, in distilled water] and left there at room temperaturefor 15 minutes. The implant is then rinsed with pure water and dried.

The implant prepared according to the preparations B(i), B(ii), andB(iii) are plated with rat bone building cells, osteoblasts. Theosteogenesis is measured as (I) the cell proliferation and (II) the boneprotein synthesis. Comparative test results are given for the untreatedimplant. The results are given in Table 1. Analogous results areobtained for all the phosphonic acids given herein above both on asmooth and on a rough surface. Analysis with XPS and ToF-SIMS indicatedthat a molecular (mono) layer was formed on a titanium surface as wellas on a TiO₂-surface.

TABLE 1 Total protein synthesis* after Number of cells* 8 days (cpm† ×Collagen* after 8 after 4 days 10⁴ per million days (% of totalPreparation (±SEM) cells) (±SEM) protein) (±SEM) B(i) 36108 (±2485) 94224 (±8357) 3.18 (±0.17) B(ii) 40773 (±1263) 104503 (±2863) 3.19(±0.10) B(iii) 37290 (±2852)  92361 (±8237) 2.30 (±0.29) Comparative32560 (±2485)  87842 (±3161) 2.74 (±0.18) Test *the numbers are given asan average value from three measurements for each test. † cpm = countsper minute from radio labeled proteins.

The results illustrate the improved osteogenesis of the implantsaccording to the present invention compared to the non treated implants.

EXAMPLE 3

Example 2 is repeated with the difference that the implant is treatedwith ethane-1,1,3-triphosphonic acid which has been modified by linkingthe amine terminus of a Glycine molecule to one of the phosphonategroups.

EXAMPLE 4

Examples 2 is repeated with the difference that the implant is treatwith ethane-1,1,3-triphosphonic acid which is modified by linking theamine terminus of a GRGDS cell binding polypeptide to one of thephosphonate groups.

EXAMPLE 5

Examples 2 is repeated with the difference that the compound accordingto formula (I) is ethane-1,1,3-triphosphonic acid which is modified bylinking the amine terminus (Methionine) of a human Bone MorphogenicProtein type 2 (BMP-2) to one of the phosphonate groups, which givesanalogous test results as given in Table 1.

1. An endosseous implant suitable for application to a human or animalbone, said implant having a surface made from titanium or a titaniumalloy, said surface having a smooth or rough texture, wherein saidsurface has a layer formed thereon of at least one pharmaceuticallyacceptable organic compound or an ester, an amide or a salt thereof,corresponding to the general formula (I):A-[P(O)(OH)₂]_(p)  (I), wherein A means A₁, and A₁ is a residue of alinear, branched or cyclic, saturated or unsaturated, hydrocarbonresidue with n carbon atoms, wherein n is a number from 1 to 70, wherebysaid residue is not interrupted or is interrupted by one or more oxygenand/or nitrogen atoms, wherein each residue A₁ carries p phosphonic acidgroups, and when n is 1 and p is 2: A is —CH₂—, or when n is 1: p is 3or 4, or when n is 2 to 10: p is 2, provided each phosphonic acid groupor phosphonic acid ester group is bound to a different carbon atomwithin the same molecule; or when n is 2 to 10: p is 3, 4, 5 or 6; orwhen n is 11 to 70: p is 2, 3, 4, 5 or 6; or A means A₂ and A₂ is aresidue of an amino acid or of a sequence of amino acids respectively ofa protein or of a polypeptide; or a residue of a specific drug molecule,wherein each residue A₂ carries p phosphonic acid groups, and p is 1 to6 when A₂ is a residue of an amino acid or of a sequence of amino acidsrespectively of a protein or of a polypeptide; or p is 1 or 3-6 when A₂is a residue of a specific drug molecule originally not bearing anyphosphonate group, optionally falling under the definition given for A₁.2. The implant according to claim 1, wherein A₁ is a saturatedhydrocarbon residue of the formula —(C_(n)H_(2n+2−p))—, wherein n means1 to
 70. 3. The implant according to claim 1, wherein thepharmaceutically acceptable salt is an alkali salt.
 4. The implantaccording to claim 1, wherein the pharmaceutically acceptable ester isan alkyl phosphonate, or an ethyl acetate.
 5. The implant according toclaim 1, wherein the compound of formula (I) is a polyphosphonic acid.6. The implant according to claim 4, wherein the compound of formula (I)is an ester.
 7. The implant according to claim 1, wherein the compoundof formula (I) is a Transforming Growth Factor beta (TGF-β) as definedby the members of the superfamily of growth factors, wherein each timethe peptide chain has been modified to contain at least onealkylphosphonic acid group or a derivative thereof.
 8. The implantaccording to claim 1, wherein the compound of formula (I) is a BoneMorphogenic Protein (BMP), wherein the peptide chain has been modifiedto contain at least one alkylphosphonic acid group or a derivativethereof.
 9. The implant according to claim 1, wherein the compound offormula (I) is 2-amino-4,4-bis-(diethoxy-phosphoryl)-butyric acid,2-amino-5-(diethoxy-phosphoryl)-pentanoic acid and/or2-amino-4-phosphonobutyric acid.
 10. The implant according to claim 1,wherein the compound of formula (I) is one of the principal twenty aminoacids, wherein the amino acid has been modified to contain at least onealkylphosphonic acid group or a derivative thereof.
 11. The implantaccording to claim 1, wherein the compound of formula (I) is aRGD-containing peptide, which has been modified to contain at least onealkyl-phosphonic acid group or derivative thereof.
 12. A process forproducing the implant according to claim 1, which comprises treatingsaid surface with at least one organic compound of formula (I) or anester, an amide, a salt or a mixture thereof.
 13. The implant accordingto claim 1, in the form of screws, plates, nails, pins or speciallyformed parts which may be used as prostheses in orthopaedics, forreplacing or strengthening broken or diseased bones, in dentistry, foranchoring artificial teeth, or for anchoring of bone anchored hearingprosthesis into the skeletal structure of humans and animals.
 14. Theimplant according to claim 13, wherein said implant is packed with aplastic or metallic packaging material.
 15. The implant according toclaim 14, wherein said packaging is filled with pure water containing aninorganic salt and/or a compound of the formula (I) or a salt thereof.16. The implant according to claim 1, wherein n is a number from 1 to40.
 17. The implant according to claim 1, wherein n is a number from 1to
 22. 18. The implant according to claim 1, wherein when n is 1, p is3.
 19. The implant according to claim 1, wherein when n is 2, p is 3, 4or
 5. 20. The implant according to claim 1, wherein when n is 2, p is 3or
 4. 21. The implant according to claim 1, wherein when n is 11 to 70,p is 2, 3, 4 or
 5. 22. The implant according to claim 1, wherein when nis 11 to 70, p is 2, 3 or
 4. 23. The implant according to claim 1,wherein A₂ is a residue of the superfamily of Transforming Growth Factorbeta (TGF-β).
 24. The implant according to claim 1, wherein p is 1, 2, 3or 4 when A₂ is a residue of an amino acid or of a sequence of aminoacids respectively of a protein or a polypeptide.
 25. The implantaccording to claim 1, wherein p is 1, 2 or 3 when A₂ is a residue of anamino acid or of a sequence of amino acids respectively of a protein ora polypeptide.
 26. The implant according to claim 1, wherein p is 1 whenA₂ is a residue of a specific drug molecule originally not bearing anyphosphonate group, optionally falling under the definition given for A₁.27. The implant according to claim 2, wherein n is 1 to
 40. 28. Theimplant according to claim 2, wherein n is 1 to
 22. 29. The implantaccording to claim 3, wherein the salt is a sodium or potassium salt.30. The implant according to claim 5, wherein the polyphosphonic acid isselected from the group consisting of methylenediphosphonic acid,ethane-1,2-diphosphonic acid, propane-1,3-diphosphonic acid,propane-1,3-diphosphonic acid, ethane-1,1,2-triphosphonic acid,butane-1,1,4-triphosphonic acid, pentane-1,1,5-triphosphonic acid,pentane-2,2,5-triphosphonic acid, hexane-2,2,6-triphosphonic acid,pentane-1,1,5,5-tetraphosphonic acid, heptane-1,4,4,7-tetraphosphonicacid, propane-1,1,3,3-tetraphosphonic acid,nonane-1,5,5,9-tetraphosphonic acid, an ester thereof, a salt thereof,and a mixture thereof.
 31. The implant according to claim 6, wherein theester is selected from the group consisting of tetra isopropylmethylenediphosphonate, hexaethyl ethane-1,1,2-triphosphonate,hexaisopropyl butane-1,1,4-triphosphonate, hexaisopropylpentane-1,1,5-triphosphonate, hexaisopropylpentane-2,2,5-triphosphonate, hexaisopropyl hexane-2,2,6-triphosphonate,octaisopropyl propane-1,1,3,3-tetraphosphonate, octaisopropylheptane-1,4,4,7-tetraphosphonate and octaisopropylnonane-1,5,5,9-tetraphosphonate.
 32. The implant according to claim 7,wherein the compound of formula (I) is a Transforming Growth Factor beta(TGF-β) as defined by the members of the superfamily of growth factors,selected from the group consisting of TGF-β1, TGF-β2, TGF-β3, TGF-β4 andTGF-β5, wherein each time the peptide chain has been modified to containat least one alkylphosphonic acid group or an ester, an amide or a saltthereof.
 33. The implant according to claim 8, wherein the compound offormula (I) is a Bone Morphogenic Protein (BMP), selected from the groupconsisting of BMP-2 (BMP-2a), BMP-3, BMP-4 (BMP-2b), BMP-5, BMP-6, BMP-7(OP-1), BMP-8 (OP-2), BMP-9, BMP-10, BMP-11, BMP-12 and BMP-13, whereinthe peptide chain has been modified to contain at least onealkylphosphonic acid group or an ester, an amide or a salt thereof. 34.The implant according to claim 10, wherein the compound of formula (I)is selected from the group consisting of arginine, glycine, asparticacid, alanine, valine, proline, serine, threonine, cysteine and lysine,wherein the amino acid has been modified to contain at least onealkylphosphonic acid group or an ester, an amide or a salt thereof. 35.The implant according to claim 11, wherein the compound of formula (I)is selected from the group consisting of a RGDS-peptide, aGRGDS-peptide, a RGDV-peptide, a RGDE-peptide, a RGDT-peptide, and amixture thereof, which has been modified to contain at least onealkyl-phosphonic acid group or an ester, an amide or a salt thereof. 36.The implant according to claim 14, wherein said implant is packed with aplastic or metallic packaging material, into an air tight packagingwhich is evacuated or filled with an inert gas or an inert liquid. 37.The implant according to claim 36, wherein said air tight packaging isfilled with pure water containing an inorganic alkali salt and/or acompound of the formula (I) or a salt thereof in a concentration of fromabout 1.0×10⁻⁵ mol/10 ml to 5×10⁻² mol/10 ml, of the water.
 38. Theimplant according to claim 36, wherein said air tight packaging isfilled with pure water containing an inorganic alkali salt and/or acompound of the formula (I) or a salt thereof in a concentration of fromabout 5×10⁻⁴ mol/10 ml to 2.0×10⁻² mol/10 ml of the water.